Neurodegenerative disorder, such as Alzheimer's Disease and Parkinson's Disease (PD), afflict a large number of our elderly population. PD is a neurodegenerative disease of unknown etiology characterized by a massive loss of nigrostriatal dopaminergic neurons. Recently, several young individuals developed a Parkinsonian syndrome following the inadvertent self-administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Indeed, the administration of MPTP to experimental animals results in damage to nigrostriatal dopaminergic neurons. These findings have led to the hypothesis that MPTP-like compounds may be responsible for the neurodegeneration of dopaminergic neuron in idiopathic PD. However, damage to nigrostriatal dopaminergic neurons in experimental animals can also be produced by the administration of methamphetamine (METH). The mode of action of METH differs from that of MPTP. Whereas the neurotoxic action of MPTP depend on the formation and action of its metabolite, MPP+, those of METH appear to depend on the actions and/or presence of the endogenous neurotransmitter, dopamine (DA). The possibility that DA itself may cause neurodegeneration has important implications for PD. The overall aims of this research project are to compare and contrast the neurotoxic actions of various dopaminergic neurotoxins, including MPTP, several of its analogs, and METH by measuring biochemical markers of dopaminergic function (i.e., DA and metabolite levels, tyrosine hydroxylase activity, DA transport capacity). Pharmacological agents which block enzymes, transport systems and receptors will be used to elucidate similarities and differences in the modes of action of the neurotoxins. A second and very important goal is to determine if older mice are more sensitive than younger mice to these various neurotoxins and if so, what might account for these age-related differences in sensitivity. A third goal is to determine if and how excitatory amino acids, which are involved with neurodegeneration in a variety of disorders, might contribute to dopaminergic cell death and whether or not there are age related differences in their excitotoxic actions. An overall goal underlying this entire project is to determine if there are similarities in the etiology of idiopathic Parkinson's Disease in humans.